Adenosine regulates a wide range of physiological functions through interaction with at least two major classes of adenosine receptors. The A1 class of adenosine receptors is inhibitory to adenylate cyclase, while the A2 class is stimulatory to adenylate cyclase. Subclasses of adenosine receptors also occur. Some of these are inhibitory to calcium channels, some are stimulatory to potassium channels, some activate guanylate cyclase, some modulate phospholipid turn-over and some cause smooth muscle relaxation. Adenoregulin, a peptide isolated from an Amazonian hylid frog, markedly stimulates binding of agonists to A1, alpha2 and 5-HT1A receptors. All of these receptors are coupled via Gi- class proteins to adenylate cyclase. Adenoregulin at higher concentrations (>10 micromoles) inhibits binding. The effects of adenoregulin appear related to alterations in receptor-G protein coupling, perhaps by enhancing such coupling. Another amphiphilic peptide mastoparan has similar effects on binding. Functional correlates with respect to effects of these peptides on adenylate cyclase have not been obtained, while stimulatory effects on calcium influx, transmitter release, and phosphoinositide are manifest for both peptides, but only at higher concentrations. Effects on phosphoinositide breakdown may relate to stimulation of calcium influx. In membranes and permeabilized cells both peptides are inhibitory to phosphoinositide breakdown. Structure activity relationships for adenosine analogs and xanthines have been further defined for A1 receptors of fat and brain, for A2a receptors of striatum, pheochromocytoma cells and human platelets, and for A2b receptors of fibroblasts. Certain analogs of caffeine are 4 to 5-fold more potent than caffeine in eliciting release of intracellular calcium. Chronic caffeine ingestion markedly alters density of many brain receptors and of calcium channels in parallel with changes in behavioral responses to adenosine analogs, xanthines, and cholinergic agents. High doses of caffeine elicit choreiform movements in mice and these are markedly reduced after chronic caffeine.